Hello. My name is Aneesh Mehta. I am an Assistant Professor of Medicine at the Emory School of Medicine. And I'm happy to be here today to speak with you about therapeutics for Ebola, on behalf of our team at the Emory Serious Communicable Diseases Unit. There are four main types of therapeutics that we are using for taking care of patients with Ebola. Those include supportive care, passive immunity, pharmaceutical, typical pharmaceutical agents, as well as vaccines. Today I'll be covering the first three topics. Vaccines will be covered in a separate lecture. So starting with our share, supportive care our mainstay of therapeutics for Ebola. Aggressive supportive care has been the only proven therapeutic to affect the outcomes of patients with Ebola. And those would include volume and electrolyte replacement, maintenance of blood pressure, maintenance of oxygen levels in the body and very good nu, nutritional support to support the reparative mechanisms of the body. And then also treatment for secondary or co-infections that may occur in these patients. So talking now about volume and electrolyte losses. Why this occurs is because patients with Ebola have very severe vomiting and diarrhea, particularly in the height of their illness, and they can be losing up to 10 liters of fluids a day through their vomiting and diarrhea. And this leads to significant dehydration, loss of fluid, from all the different parts of the body. And then that leads to electrolyte losses and loss of nutritional status of the body. Also, as the disease progresses and the virus invades other areas of the body, you get this phenomenon known as vascular leak, where the blood vessels of the body start leaking fluids into different spaces, what we call third spaces of the body. And combined with low albumin, you start to see all this volume of fluid in areas of the body where it's not helpful, and, and removed from the blood circulation where the body needs it to support the reparative mechanisms and the immune system. So how we replace volume and electrolytes are by multiple methods. First, we try to rehydrate the patients through fluids that you would take in. So that would include water, rehydration fluids such as the WHO ORS fluid, or Gatorade or similar products. But some of these patients are even more volume depleted than we can replace by mouth, and so we have to use intravenous fluids. And that's where we place an IV into one of the veins of the body and we give them fluids. If they're having high volumes of diarrhea we give a fluid called lactated ringers which is a nice, balanced fluid to help replace the losses that you typically get with diarrhea. Otherwise, we use normal saline, particularly if their sodium levels are low in the body. And our goal is to really balance the losses of electrolytes and fluids without over-correcting, which can often happen if we're not being very careful. And then, in addition, we, these patients, as I mentioned, are losing electrolytes, and electrolytes are things like sodium, magnesium, potassium, calcium. And they're losing this because they're having diarrhea, they're vomiting, and they're also not able to take in nutrition because of the amount of nausea that they're having. And so we have to use both oral replacement and, again, intravenous replacement. And these can be with the types of fluids that we mentioned, but also we can give them the specific electrolyte if we know by our laboratory testing that they're low on something like magnesium. And then we can also supplement their nutrition in specific ways to boost those particular electrolytes and micronutrients that they may be losing. So we do have other supportive care measures that I've alluded to before. And very importantly for these patients with Ebola is supporting their nutritional styles. And the first mechanism that we use to do this is actually nausea medication to control their nausea and vomiting so that we can give them oral supplementation and nutrition. We also use liquid nutrition and liquid supplements, such as vitamins, minerals, and micronutrients. And we use these formulations because they're easy for the body to absorb, even when they're under damage of the Ebola virus infection. Though some patients are even more ill, and particularly, in our critical, critically ill patients, we have to use something known as TPN or Total Parenteral Nutrition. And this is a cocktail of different nutrients that are put into an IV fluid bag and given slowly over a course of 24 hours to the patient. Another supportive care measure that's important, particularly in patients with Ebola, is correction of coagulopathies. And what coagulopathies are bleeding disorders or bleeding dysfunction. And again, nutritional support will help with this, but some patients will need transfusions of platelets, particularly if their platelets drop below 50,000 in the blood. And in addition, we use a product known as fresh frozen plasma if we are seeing signs of bleeding. And this replaces some of the clotting factors to help their body stop that bleeding and get good clots. So our next main area of therapeutics for Ebola would be something we term as passive immunity. And passive immunity has been used for infections for decades. Passive immunity has been used for types of infections particularly viral infections such as CMV, or cytomegalovirus, different types of hepatitis infections. It's, it is still used for rabies and tetanus infections, and in children for things like chicken pox and it is now also being used for influenza infections. So we have two types of ther, of passive immunity when we're talking about Ebola-type infections. And the first one being using blood products from those that are recovered from Ebola, something known as convalescent blood products, or convalescent plasma. And you might hear a lot about this, because there's a lot of interest in using the blood from recovered patients to help acutely sick patients. And another area of passive immunity are something known as pooled antibodies. And that's where we take antibodies that we know work against Ebola usually from patients who have recovered, and concentrate them down to try to have a more direct impact on the virus. So convalescent plasma or convalescent blood products have been used for Ebola viral infections in the past. And the, the most data that we have is from a 1995 outbreak of Ebola virus in Kikwit where eight patients received convalescent whole blood transfusions. And following this treatment, seven of those patients survived, giving an overall case mortality of 12.5% which was much better compared to the overall mortality at that outbreak and also compared to previous outbreaks. But there a big caveat to that experience, in that the patients that were enrolled in the study received much better care, much more intensive care than the control patients, or the other patients during that outbreak. So it was really hard for us as a scientific and medical community to determine how much of the impact of those that survival benefit was from the convalescent blood. In addition, when they've used whole blood in animal models in Ebola and similar-type infections, they haven't been able to consistently demonstrate a benefit of that convalescent blood product. However, we believe that convalescent plasma may have better activity than whole blood because it's a higher concentration of antibodies, with less interfering agents that might be present in whole blood. However, to date, there have not been good studies evaluating convalescent plasma for Ebola. But it has been used in several patients. But because it was not used in a study setting the issues of control were not there, and so we're unclear at this time if it has any effect or not. But fortunately there are many ongoing studies here in the United States as well as in West Africa and in Europe, trying to evaluate the efficacy of convalescent blood products for patients with Ebola. So now, moving into some of our pooled antibodies, or our antibody cocktails. The big one that has been discussed in this outbreak is a product named ZMapp, and that was developed by Mapp Pharmaceuticals. And this a combination of three chimeric human mouse antibodies. And they're a specific type of antibodies known as IGG1 antibodies. So this is a combination, or a cocktail of these three monoclonal antibodies that are all targeted against the very distinct region of the Ebola virus known as the GP protein. And the method used to produce these antibodies is also fairly unique. It's made in a tobacco plant that has been specifically engineered to produce these antibodies in its daily cell cycle. All three of the antibodies used in this cocktail have demonstrated good neutralizing activity, meaning they are able to bind to the virus and help bring that virus to the immune system before it can infect other cells of the body. And there's been a very interesting study just recently published where, in an animal model, they are able to ser, save, 100% of Macaque monkeys that were infected with Ebola, even when they started the medication five days after infection. And that's far better efficacy than any other modality of therapy that's ever been shown in that model. We have been able to use ZMapp, this cocktail of three antibodies, in several patients seven patients in total now, in the US, Europe and in West Africa. These were all used under a compassionate use protocol from the company and from the FDA. And unfortunately, because these were, again, not per, given in a study setting without controlling for all the confounders, we don't have any data really to determine the efficacy of the medication. Fortunately we do now have a randomized control trial in patients that will be starting both in the US and in Liberia that is sponsored by the NIH, and we hope that will produce data to let us know whether this product is truly useful. There are also other antibodies that are being used, for Ebola virus infections. And the two main ones are actually the predecessors of the ZMapp cocktail. One being known as MB-003, again from Mapp Biopharmaceuticals. And this is also a combination of three human-mouse chimeric monoclonal antibodies. And it has also been shown to save monkeys in that same monkey model, save monkeys that are affected with Ebola only the, within one hour of infection. The one most active antibody was pulled out of this cocktail and used for ZMapp. The other preparation that has been studied is something that is known as ZMab. And that was from Defyrus Pharmaceuticals. And this is a company the combination of three mouse monoclonal antibodies, so no human components to these antibodies at all. And they were also able to demonstrate 100% survival in the monkeys that were infected, again, within 24 hours of treatment. And also from this cocktail, the two most active antibodies were pulled out and then partially humanized and then used in the ZMapp cocktail. So again ZMapp has put, pulled together the best antibodies from the previous cocktail, hopefully to increase the activity of their overall, the newer cocktail. So finally the main ar, the other area that we're going to talk about today are our pharmaceutical agents, our classic biochemical agents. The first one I'd like to talk about is a product known as Tekmira-Ebola produced by Tekmira Pharmaceuticals. And this is a small interfering ribonucleic acid or siRNA product. And this is a type of double-stranded RNA that binds to target genes on the virus, and silences them through a process known as enzymatic cleavage. And it specifically cleaves and destroys the messenger RNA of the virus. And in this product they have two species, or two types of siRNA products, that target two different genes to help stop the replication of the Ebola virus. And this has been studied now in monkeys that have been infected with Ebola and demonstrated high rates of survival when the monkeys have been treated within 72 hours of them being infected. It has, in addition, now been used in a few patients in the United States and Europe who have been evacuated from West Africa. And, there is an on, there is preparation for a trial that will start soon in West Africa, again, to determine to determine the efficacy of this medication in Ebola-infected individuals. The next product is Favipiravir, or T-705. It's a product from Toyama, Chemicals. And it was initially developed as a broad-spectrum antiviral, as it inhibits viral RNA-dependent RNA polymerase. And this was initially tested against influenza viruses, but since that time has also been tested over a slew of other viruses such as flaviviruses, arenaviruses and enteroviruses, in addition to many others. And recently, there was a trial in Guinea in West Africa, known as the JIKA trial, and in that trial they found that while it was overall safe, they did not find a clear difference in the survival between patients who receive this drug and those who didn't. But in an analysis of, a subanalysis of this product in this trial, they did show that there was a potential benefit for patients who presented with very low levels of the virus in their body who were not quite ill yet. And so there may be some benefit down the road for this product. The third agent that we're going to talk about is known as BCX4430. It's a product of Biocryst. And this is a nucleic, nu, nucleoside analogue that inhibits, again, viral RNA-dependent RNA polymerase, blocking the replication of the virus. This is also a broad-spectrum antiviral tested against multiple families of viruses including influenza viruses, flaviviruses, coronaviruses, etc. And at this time, the product is early in development and is just starting studies in the monkey models of Ebola infections. And so we hope to receive data from these nonhuman primate studies so that we can move forward into phase one human studies. So the next product is AVI-7537 and this is a new type of molecule known as a positively charged morpholino oligomer, otherwise known as PMO. And this binds to viral mRNA from the virus, and prevents its translation to make the proteins that the virus will need for its lifecycle. And in nonhuman primate studies, it has demonstrated very good survival of monkeys infected with Ebola, depending on the time they were infected to the time that they receive the medication. Again, this medication is early in development and there are no human studies that have started yet. There are several great references to read more about Ebola therapeutics. The WHO puts out a a reference on its website that is updated periodically and it's termed the Potential Ebola Therapeutics and Vaccines. And also there's a wonderful review in Trends in Microbiology from August of 2014 with the first author G Wong, that also details these products that I've talked about in much greater detail. So now we've reviewed three main areas of therapeutics for Ebola. As I mentioned at the beginning, the mainstay of therapy is supportive care, but we hope as this outbreak progresses we will learn more about additional options to take care of these patients. And the data will be forthcoming, and it is a really exciting area. So I thank you for taking the time to listen to this lecture today on therapeutics for Ebola virus infections.
